Implantable solid dosage form

ABSTRACT

A solid dose for insertion into the skin of a patient wherein the solid dose has a hollow core. There is also provided a solid dose carrier, a device, a method of manufacturing the solid dose and a method of delivering a solid dose transdermally to a human or animal.

The invention relates to the transdermal delivery of drugs to a patient.In particular, it relates to the delivery of a solid dose into the skinof a patient.

Syringes and needles have been widely used to deliver drugs to apatient. The patient may be human or animal. This requires skilledpersonnel to deliver the drug and there is a period of time associatedwith the delivery of drugs using such a technique during which thedevice must be resident in the skin to allow complete delivery of thedose inside the skin. Microneedle technologies allow the delivery of asmaller mass of drug carried by one or more needles into the skin.However the microneedle technology also faces the issue of prolongedskin insertion, which is required for the drug to dissolve into the skinfrom the surface of the needle as the drug is adhered or coated to theneedle, or the needle is produced from the drug.

Glide Pharma (see applications US 2011/0313348, and US 2010/0119570)have developed a device that allows the instant delivery of a solid doseinto the skin. However the solid dose must have the requisite propertiesto maintain tip sharpness and hardness to be able to penetrate the skin.The drug pellet is directly inserted into the skin using a devicedescribed as having a pointed or chisel shaped tip, which is forced intothe skin using a spring loaded mechanism to provide the requisiteinsertion force such that the tip of the drug pellet is able to overcomethe mechanical barrier posed by the drug.

However, most drugs do not lend themselves to the qualities required fordirect skin insertion, and the use of large amounts of polymers andcarbohydrate based excipients to enhance the mechanical strength of saiddrug pellets act to limit the drug loading reducing its practicalutility. This is a major impediment of such a device.

WO2006/082439 describes a device with a skin piercing projectile whichfirst enters the skin followed by the solid drug formulation immediatelybehind, as an integrated unit, whereby the skin projectile is a part ofthe solid dose, albeit an inert part of it with the function of piercingthe skin and eventually dissolving and being absorbed into the body.WO2012/098356 describes a means of first cutting the skin using a blade,followed by the insertion of the drug into the skin. This is essentiallyidentical in principle to the disclosure in WO2012/035334, filed by thepresent applicant, describing a device that first creates an opening inthe skin followed by the insertion of the drug.

Other devices such as that described in PCT/US2000/015312 describe theloading of drugs in a slit built into the tip region of the needle, orin another case to the side of a needle with a cavity that had beenetched out to hold the drug. However, given that the drug must be heldwithin that cavity and must dissolve in the skin to be released into theskin, it does not provide for instant delivery, depth and duration ofskin insertion which will ultimately affect the extent of drugabsorption.

It is preferable to have a device that allows for skin insertion of asolid dose without the need for the drug to have properties which havehigh mechanical strength and properties that lend the drug to beinginserted directly into the skin, and one that allows instant skindelivery of a solid dose. It would be preferable to be able to insertdrug doses into the skin using a single motion that may or may notrequire an insertion rod to deposit the solid dose into the skin, andone that may or may not require additional mechanical force from asupplementary device or mechanism such as a spring or pneumatic forcefor example.

Furthermore it would be preferable to be able to deliver a solid dosewith an enlarged surface area that enhances the speed of dissolution ofthe solid drug once inside the skin and in contact with the interstitialfluid or micro circulation in the skin, or one that provides a greaterdegree of control and consistency over sustained drug release profiles.

This invention describes a solid dose that is seated around a carrierwith a hollow core through which the carrier protrudes with a portion inthe distal region of the carrier which is able to pierce the skin toremove the barrier to skin-insertion of a solid dose, thereby allowingfor the dose to be delivered with low force, to a defined depth andinstantly without the need for any residence time of the carrier insidethe skin once the solid dose has been inserted.

By “defined depth” the skilled person would understand this term to meanat a depth of the skin which would allow release of the ‘activeingredient’, and/or absorption of the solid dose into the human oranimal body.

As used herein, the term “transdermal” means the route of administrationwherein active ingredients are delivered across the skin for local orsystemic distribution.

The “skin” is defined here as a biological membrane, such as the stratumcorneum, oral mucosa, ocular membrane, or other mucosal membrane on thesurface of the body of the subject, or within a cavity or abdomen of thepatient (e.g., applied during surgery).

According to the present invention, there is provided a solid dose forinsertion into the skin of a patient wherein the solid dose has a hollowcore.

Preferably, the solid dose has a shape which allows delivery of thesolid dose into the skin, wherein the shape is conical, frustoconical,cylindrical or a cuboid.

Optionally, the solid dose comprises a proximal end and a distal end,and wherein the distal end of the solid dose is tapered. The solid dosecan also be elongated with an aspect ratio of greater than 1.

Preferably, the solid dose comprises at least one active ingredient.Optionally, the solid dose comprises at least one excipient. Inaccordance with one embodiment, the solid dose consists of an activeingredient.

Preferably, the length of the solid dose is less than 1000 microns.Optionally, the dose is between 10 microns to 20 mm in length.

Optionally, the solid dose is coated with a biodegradable polymer or acarbohydrate. In accordance with the present invention the solid dosecan be soluble or biodegradable.

In accordance with a further aspect of the present invention, there isprovided a solid dose carrier for the skin insertion of a solid dose asdefined herein, wherein the solid dose carrier comprises a proximalportion and a distal portion, wherein the solid dose can be seated on oraround the distal portion of the carrier, and wherein the distal portionof the carrier is capable of penetrating the surface of the skin toallow insertion of the solid dose in to the skin.

In one embodiment, the carrier further comprises an insertion mechanismto assist with insertion of the solid dose, wherein the insertionmechanism is adapted to move relative to the carrier and so act toprovide resistance to the movement of the solid dose away from the skinas the carrier is pushed into the skin. Optionally, the insertionmechanism is a sleeve which is either partially or completely wrappedaround the carrier.

Preferably, the proximal portion of the carrier has a cylindrical shapeand the distal portion is capable of penetrating the skin. Morepreferably wherein the solid dose carrier is a needle.

Optionally, the solid dose carrier is capable of delivering single ormultiple doses either consecutively or simultaneously.

Preferably, the solid dose carrier further comprises a solid dose whichis seated on or around the distal portion of the carrier.

In accordance with a further aspect of the present invention, there isprovided a device for the skin insertion of a solid dose, wherein thedevice comprises a solid dose carrier as defined herein.

Preferably, the device according to the present invention comprises alower portion comprising the solid dose carrier and further comprises anupper portion to allow the user to press the device into the skin. Thelower portion of the device can also comprise a platform, wherein thesolid dose carrier is connected to the platform, and wherein theplatform is intended to define the maximum depth of penetration of thesolid dose carrier into the skin.

In one embodiment, the device further comprises an outer case comprisingone or more cavities, and the upper portion of the device furthercomprises one or more protrusions, wherein the cavities receive theprotrusions to provide resistance to the movement of the device as it ispushed into the skin. Optionally, the outer case further comprises abottom rib which sits against the skin and provides a means to fix thepressure that is applied to the device to ensure insertion.

In a further embodiment, the device comprises one or more solid dosecarriers carrying one or more solid doses. In another embodiment thedevice is a single use disposable unit.

In accordance with a further aspect of the present invention, there isprovided a method of manufacturing a solid dose as defined hereincomprising the following steps:

-   -   (i) providing the solid dose ingredients; and    -   (ii) shaping the solid dose.

Preferably, the shaping step involves using a method selected from wetcasting, direct compression molding or extrusion. Optionally, theshaping step involves compression molding using a multipart tool. Themethod can also comprise a step of forming a hollow core of the soliddose.

Optionally, the method further comprises the steps of

-   -   (i) placing the solid dose ingredients into a multipart die;    -   (ii) pressing a punch section comprising a pin into the die        section to form the hollow core of the solid dose;    -   (iii) optionally rotating either the pin or the die multiparts;        and    -   (iv) ejecting the formed solid dose from the die.

In accordance with another aspect of the present invention, there isprovided a further method of manufacturing a solid dose as definedherein comprising the following steps:

-   -   (i) coating the solid dose carrier with a lubricant;    -   (ii) coating the solid dose carrier with the dose ingredients        which are in the form of a liquid, paste or mixture; and    -   (iii) drying the coating to form the solid dose.

In a further aspect of the present invention, there is provided a methodof delivering a solid dose transdermally to a human or animal using thedevice as defined herein comprising the steps of:

-   -   (i) pressing the carrier carrying the at least one solid dose        into the skin of the human or animal;    -   (ii) pushing the carrier and solid dose into the skin to a        desired depth; and    -   (iii) withdrawing the carrier to leave the solid dose in the        human or animal.

Optionally, multiple solid doses are delivered consecutively orsimultaneously using the carrier.

A solid dose of this form allows skin insertion without the tip of thesolid dose requiring any specific restrictions to the angle or sharpnessto pierce the skin nor the mechanical strength to withstand thecompressive forces it will experience when pressed into the skin. Soliddoses directly inserted into the skin, relying on their own inherent tipsharpness are liable to break at the tip leading to a blunt tipresulting in significant trauma on the skin and to the patient and alsocreates potential for poor and inaccurate dosing.

A major benefit of this type of solid dose is that the hollow core isless likely to experience rapid bio-fouling, as would be experienced onthe surface of the solid dose, (and as is experienced for needle likeglucose sensors that are used for continuous glucose monitoring wherebydrift is observed due to the bio-fouling effect), leading to furtherrefinement over the consistency of drug release where a sustainedrelease profile is desired over days or weeks for example.

The skilled person would understand the term “solid dose” to describe apharmaceutical dosage form. More specifically this term is used todescribe a dose that is formed as a mass that is predominantly solidwhich comprises one or more active ingredients but may also containexcipients such as solvents that act as binding agents, solubilityenhancing agents, permeation enhancing agents and other liquids that maybe required to achieve the desired rapid or sustained release profile.The solid dose may be composed of a wide range of excipients that areestablished and documented for tablet manufacture by direct compression,granulation, or micro-molding and micro-replication techniques.

By the term “active ingredient” we mean a biologically active substancethat has a therapeutic or cosmetic effect. Biologically activesubstances can include small molecules, proteins and peptides. Inparticular, the active ingredient can be selected from, but not limitedto vaccines, cosmetic agents (such as Botulinum Toxin), pain-reliefdrugs (such as opioid analgaesics, triptans and NSAID's), hormones (suchas Human growth hormone or hydrocortisone), vitamins, anaesthetics,antihypertensive agents and contraceptive agents.

To produce solid doses of the desired shape, wet casting techniques maybe used. In particular, a suitable mold may be used followed by dryingthe wet mass, or by extruding as a hollow cylinder followed by cuttingto the requisite length. One benefit of using wet molding or extrusionis that upon drying, the solid mass will undergo a certain amount ofshrinkage, which will be consistent for a given set of processingconditions and formulation composition, thus reducing the need for highprecision tooling with fine tolerances, since a slightly larger soliddose may be prepared and a controlled shrinkage will lead to a smallerdose size on drying.

The solid dose may be any size which is suitable for delivery by thesolid dose carrier, and so if, for example, the solid dose carrier is aneedle, the solid dose will be restricted by the size of the needle. Thesize is also restricted by the physical limitation imposed by methodsused to produce the solid dose that will enable the solid dose to retainits mechanical properties; this may be in the region of 0.1 mm soliddose wall thickness. In some embodiments, the solid dose may have a sizeof less than 1000 microns, or preferably between about 10 microns toabout 20 mm in length. Preferably, the solid dose is in the form of apellet.

If the dosage of active ingredient to be administered to a patient istoo large, then it can be administered as multiple solid doses, and ifrequired over multiple solid dose carriers.

In some instances of the present invention, the smallest size solid dosemay in fact be produced using a completely different process than thecasting or extrusion techniques which have been described above.

An alternative method for forming a solid dose can be described usingthe following steps:

-   (i) coating the solid dose carrier with a lubricant;-   (ii) coating the solid dose carrier with the dose ingredients which    are in the form of a liquid, paste or mixture; and-   (iii) drying the coating to form the solid dose.

The purpose of the lubricant in the above described method is to preventthe solid dose from sticking to the solid dose carrier. The lubricantswhich can be used are described below. The coating can be air dried orby using hot air drying techniques.

When using the above method, a shroud is formed around the solid dosecarrier that is solidified. The shroud preferably has a thickness offrom 10 to 20 urn. However, the shroud can be far thinner and smallerthan the solid doses which are produced using the direct compressiontechnique. The major advantage of this technique is that very thin soliddoses can be produced.

In accordance with the present invention, the lubricants, anti-adherantsand glidants that can be used are well known to the skilled personworking in the field of formulations and tableting. Examples oflubricants include, but are not limited to oil based lubricants such asmineral oils, powder lubricants and glidants. Preferably, the lubricantis selected from one or more of magnesium stearate, calcium stearate,stearic acid, hydrogenated vegetable oil (for example Sterotex®,Lubritab® and Cutina®), mineral oil, polyethylene glycol (for examplePEG 4000-6000), sodium lauryl sulfate, glyceryl palmitostearate(Precirol®), glyceryl behenate (Compitrol 888 ®) and sodium stearylfumarate.

Preferably the anti-adherant and glidant is selected from talc or fumedsilicon dioxide.

The solid dose may also be composed of drug alone where the drug is asolid with the appropriate properties for being converted into a soliddose with a hollow core. The shape of the solid dose may include ahollow cone, a hollow cylinder, a hollow sphere, hollow rectangle,hollow frustoconical, hollow cuboid or indeed any shape with one or morefaces. It may be preferable that where the solid dose is large, e.g.,for administration to animals where the dose may be several millimetersin length. Additionally the dose may be elongated, i.e., to have anaspect ratio greater than 1. The solid dose in accordance with thepresent invention may contain a leading edge (that will first enter theskin) that does not contain any sharp corners, but instead may have arounded edge or an irregular shaped edge.

As used herein, the term “hollow” is used to mean a cavity which extendsfrom the proximal end towards the distal end of the solid dose. Thecavity can extend partly or completely from the proximal end to thedistal end of the solid dose. Preferably, the hollow core extendscompletely from the proximal end to the distal end of the solid dose.

The objective of the present invention is to prevent the leading edgefrom providing large frictional forces or obstruction to the entry ofthe solid dose. The size of the solid dose may vary from sub-millimeterto over 10 mm. Preferably wherein the diameter of the solid dose is from10 microns to about 20 mm, or about 0.01 mm to 15 mm, more preferablyfrom 0.5 mm to 10 mm, and still more preferably from 1 mm to 5 mm. Inone embodiment, the solid dose has a conical shape and is hollow.Preferably the solid dose has an outer width at the top of the cone of0.5 mm, and a length of 0.8 mm. The sub-millimeter solid dose ispreferably prepared using micro-molding techniques widely employed formicroneedle production, and the larger sized solid dose is preferablyprepared using more conventional compression techniques.

For the manufacture process of the solid dose, where compression orpressure molding techniques are used, it would be preferable that amultipart tool is used in particular for solid doses with dimensions inthe sub-7-8 mm length range. It has been found that solid doses of thissize range and lower are difficult to remove from the mold tooling. Inthe event where the mold tooling is electro polished on the interiorsurface, the reduction in friction rapidly wears off and the solid dosescannot be readily ejected from the tool.

Additionally a pin can be used to form the hollow core of the soliddose. It has also been demonstrated that rotation of the mold cavityand/or the pin (in opposing directions) during compression, furtherfacilitates the formation of a solid dose with smooth surfaceproperties, and is readily ejected from the tool after its formation bycompression.

Furthermore enhanced mechanical properties are achieved due to bettercompaction when the solid mass for the solid dose is placed into the(multipart) die prior to the die completely closing up to form thedesired cavity. The punch section with a pin is then pressed into thedie section simultaneously as the die section closes to form the soliddose wall cavity; the die multi-parts may also be rotating as they closeto form the cavity for the solid dose.

A further embodiment of the invention is whereby the solid dose iscoated with a biodegradable polymer, carbohydrate or other material thatprovides a high level of toughness and resistance to compressive forcesand any resistance that may be experienced as the dose passes throughthe skin. Types of tablet coatings would be well known to the skilledperson and can include sugar coatings and film coatings. Such coatingsare already practiced in the drug tabletting field whereby the coatingeither reduces the friability of a tablet or imparts controlled orsustained release properties to the tablet; the same principle can beapplied to the present invention.

In accordance with a further embodiment of the present invention, toprevent the breakage of the leading regions, the solid dose may betapered, thus thinner) towards the distal end (otherwise known as theleading end which is the portion of the solid dose that first enters theskin). The solid dose may be tapered to less than 50 microns, and morepreferably less than 10 microns.

The solid dose may be inserted into the skin after the entry of theprotruding portion of the carrier, with resistance to movement of thesolid dose further up the carrier provided by a flat edge against whichthe proximal portion of the solid dose rests on the carrier. It may alsobe further pushed into the skin if desired using an insertion mechanismwhich may be a sleeve around the carrier which is able to move relativeto the carrier, where the sleeve may be partially or completely wrappedaround the carrier. In this case the sleeve would act to provide theresistance to movement of the solid dose away from the skin as thecarrier is pushed into the skin.

The solid dose carrier may be an injection device that is predominantlycylindrical in shape such as a needle, with a leading tip, that may bepointed or flat, that has the requisite sharpness to penetrate the skin.The carrier may also have a flat wall, such as a lancet, or somecombination of wall contours that provide the requisite physicaldimensions to enable a hollow solid dose to be positioned over thecarrier for the purposes of being inserted into the skin of a human oranimal. A single or multiple solid doses may be delivered from a singledevice, in a single motion, consecutively or simultaneously as required,i.e., the device may have one or more carrier.

According to the present invention, the solid dose carrier can be fromabout 0.1 mm to about 1 mm in diameter. In some embodiments, the carriercan have a diameter of greater than >1 mm diameter e.g., for animalvaccines it could be 2-3 mm diameter. The carrier from which the carriercomprises can include a metal (e.g stainless steel. Alternatively thecarrier can be comprised of a ceramic or polymer material.

As the person skilled in the art will appreciate, the force which isrequired by the clinician, or even the patient themselves, to push thesolid dose carrier with the solid dose into the skin is dependent uponthe size of the solid dose carrier and the size of the solid dose.

The larger the solid dose, the larger the forces will be required (forexample >20N). When smaller solid doses are carried on a smallercarrier, then generally smaller forces are required. In the case of a<0.1 mm needle with a 0.01 mm shroud thickness the force is <5N.However, other factors can also influence the force to be applied suchas the skin thickness and roughness of the human or animal patient. Sowith very rough and textured skin the force may be increased severalfold. However, the present invention does not require the very largeforces which are essential for direct insertion of the pointed or shapedsolid doses known in the art (such as those described in US2011/0313348).

BRIEF DESCRIPTION OF FIGURES

FIG. 1—Schematic of the device and solid dose delivery process.

FIG. 2—Illustration of the device indicating an upper portion forpressing down with palm, and lower portion with a needle indicated asthe carrier of the solid dose (solid dose not shown).

FIG. 3—Schematic representation of the device.

FIG. 4—Cross section of the carrier portion of the device.

FIG. 5—Schematic representation of various shapes of the solid dose.

FIG. 6—Schematic illustration of a three-part mold tool for producingthe solid dose.

FIG. 7—Schematic illustration of the mold tool and pin associated withthe compression die.

FIG. 8—Schematic illustration of the device within an outer case whichprovides resistance to the movement of the solid dose/carrier.

FIG. 9—A graph showing the release of diclofenac sodium in a pellet,formed according to the present invention, wherein the pellet comprises40% diclofenac sodium and 60% sucrose.

The device (20) according to the present invention is shown in FIG. 1 inuse and illustrates the solid dose delivery process. A solid dosecarrier (3) is shown as carrying the solid dose (5) and a sleeve (4)(indicated as an insertion rod) is shown shrouding the upper proximalportion of the carrier, and the solid drug pellet shown shrouding thedistal portion of the carrier, with a sharp tip from the carrierprotruding out from the base of the solid drug pellet. This is thenshown inserted inside the skin followed by further insertion of thesolid dose using the sleeve, and retraction of the device with the soliddose remaining inside the skin. Protrusion of the tip of the carrier maybe tens to several thousand micrometers, preferably 10 to 5,000micrometers, more preferably 20 to 2,000 micrometers and more preferably50 to 1,000 micrometers.

The depth of insertion is dependent upon the size of the solid dose. Inone aspect wherein the dose is a large dose of approximately >1 mm inlength, then the solid dose will be required to be pushed deeper intothe skin, than if it is a smaller solid dose, of approximately <1 mmlength. The depth is determined such that it is sufficient to ensure thepellet does not protrude back out of the skin. In accordance with thepresent invention, the solid dose is pushed to a depth of at least 0.5mm into the skin, preferably the solid dose is pushed to a depth ofabout 0.5 mm to about 1 mm.

In FIG. 2, the device of the present invention is shown with an uppersurface (100) for pressing down with the palm, and lower portion (110)with a needle (120) indicated as the carrier of the solid dose (soliddose not shown). The device (20) is shown as a single use disposablecomponent without any moving parts whereby a single motion of pushingthe carrier/solid dose into the skin leads to delivery of the solid doseinto the skin to a pre-defined depth.

In FIG. 3, the device (20) of the present invention is shown having anupper surface (100) which is used to apply the device by applying manualpressure to this portion. The carrier (3) with a sharp tip is shownattached to a platform (2) which is intended to define the maximum depthof penetration of the solid dose carrier.

In FIG. 4 the cross-section of the carrier portion of the device isshown with the carrier (3), solid dose insertion sleeve (movablerelative to the carrier) or restraint sleeve (fixed position relative tothe carrier) (4) and solid dose (5) shown as a hollow conical dose.

FIG. 5 illustrates that the solid dose can comprise of various shapesand dimensions which include, but are not limited to the shape of ahollow cone, hollow cocoon and hollow rectangular shape with smoothededge profile. It will be appreciated that these are mere representationsof the shapes and dimensions of the solid dose that can be produced andis not intended to be an all-encompassing representation.

The three-part mold tool for producing the solid dose is shown in FIG.6, with each of the three parts (8) shown in the open position, with theblock arrows intended to indicate the movement of the parts together.After compression the three parts are moved apart leading to the dosebeing readily ejected from the die. It will be appreciated that thethree-part tool is a representation of a multi-part tool system, and thetooling may contain one or more parts for the die section according tothe needs based on the solid dose size and geometry.

Release agents may be used to assist in removing the formed solid dosefrom the die. A suitable release agent is magnesium stearate.

FIG. 7 shows a multi-part mold tool die (8) and punch (9), and pin (13)which can be used to prepare the solid dose of the present invention.The arrow shown next to the punch is intended to indicate the punchrotating as well as moving down vertically to compact the mass into asolid dose. The arrow indicated next to the die section is intended toindicate the rotation of the die before. This rotation may be during andpossibly after the die section has closed together to form the desiredcavity.

The device (20) is shown in FIG. 8 within an outer case (40) whichprovides resistance to the movement of the solid dose/carrier. The uppersurface (100) of the main body (30) of the device (20) is shown at anelevated position relative to the outer case (40). The body (30) of thedevice is also shown with protrusions (10) on the surface to provideresistance to movement of the device as it is pushed into the skin. Thebody (30) of the device can comprise one or more protrusions (10). Theouter case (40) has a corresponding cavity in the case wall (11) whichwill seat the protrusion(s) (10) on the main device housing once thelatter has been depressed far enough. The outer casing (40) is shownwith a bottom rib (12) which seats against the skin.

This embodiment of the device provides a means to fix the pressure thatis applied to the device to ensure insertion. By designing the one ormore protrusions (10) on the main device body (30), and flexibility intothe outer case (40) such that for the drug carrier (3) to move down andinto the skin a defined force must be applied to overcome the resistancefrom the protrusion to enable the inner main device body (30) to moverelative to the outer case (40).

An added benefit of this is that once the force threshold has beenreached the carrier (3) and solid dose (5) will rapidly enter the skinthus avoiding the possibility of an operator mis-dosing due toinadequate penetration of the solid dose into the skin. This alsoprovides a means of ensuring the same device cannot be used twice on apatient, by ensuring the outer and inner case lock together at thispoint of insertion.

The present invention provides an enlarged surface area through acombination of the surface and the inner walls of the hollow core of thedosage, into which fluid from the skin will diffuse and provide rapiddissolution where desired, depending on the formulation of the dose. Thelarger surface area from which gradual erosion can occur provides agreater degree of control over the controlled or sustained release fromthe solid dose by virtue of the surface area to volume ratio i.e., thevariability of release profile for a given surface area will be reducedwith an increase in surface area.

As the skilled person will appreciate there are a wide range offormulations known in this particular field that provide a dynamic rangeover which drug release occurs. The dose may be delivered for localiseddrug delivery to the extent that it does not release fast enough forsystemic absorption, or it may be released within tens of seconds (asdemonstrated by recent dissolution studies illustrated in FIG. 9) forrapid systemic absorption.

EXAMPLE

A typical solid dose prepared according to the present inventioncontains the following ingredients:

Formulation A: Microcrystalline cellulose as key bulking agent (80% byweight), and 20% Bovine Serum Albumin, (up to 20% by weight).

The above formulation was also prepared using Pearlitol (directcompression mannitol) and sodium carboxy methyl cellulose in replacementof microcrystalline cellulose.

It was found that for the above tested formulations, the compressedsolid dose mechanical properties were acceptable for skin insertion.

1. A solid dose for insertion into the skin of a patient wherein the solid dose has a hollow core, wherein the solid dose comprises a proximal end and a distal end and, wherein the hollow core extends completely from the proximal end to the distal end of the solid dose and wherein the solid dose is configured to remain inside the skin after insertion.
 2. The solid dose according to claim 1 wherein the solid dose has a shape which allows delivery of the solid dose into the skin, wherein the shape is conical, frustoconical, cylindrical or a cuboid.
 3. The solid dose according to claim 1 wherein the distal end of the solid dose is tapered.
 4. The solid dose according to claim 1 wherein the solid dose is elongated with an aspect ratio of greater than
 1. 5. The solid dose according to claim 1 wherein the solid dose comprises at least one active ingredient.
 6. The solid dose according to claim 1 wherein the solid dose comprises at least one excipient.
 7. The solid dose according to claim 1 wherein the solid dose consists of an active ingredient.
 8. The solid dose according to claim 1 wherein the length of the solid dose is less than 1000 microns, or wherein the length of the solid dose is between 10 microns to 20 mm in length.
 9. (canceled)
 10. The solid dose according to claim 1 wherein the solid dose is coated with a biodegradable polymer or a carbohydrate.
 11. The solid dose according to claim 1 wherein the solid dose is soluble or biodegradable.
 12. A solid dose carrier for the skin insertion of a solid dose as defined in claim 1, wherein the solid dose carrier comprises a proximal portion and a distal portion, wherein the solid dose can be seated on or around the distal portion of the carrier, and wherein the distal portion of the carrier is capable of penetrating the surface of the skin to allow insertion of the solid dose into the skin.
 13. The solid dose carrier according to claim 12 wherein the carrier further comprises an insertion mechanism to assist with insertion of the solid dose, wherein the insertion mechanism is adapted to move relative to the carrier and so act to provide resistance to the movement of the solid dose away from the skin as the carrier is pushed into the skin, optionally wherein the insertion mechanism is a sleeve which is either partially or completely wrapped around the carrier.
 14. (canceled)
 15. The solid dose carrier according to claim 12 wherein the proximal portion of the carrier has a cylindrical shape and the distal portion is capable of penetrating the skin, optionally wherein the solid dose carrier is a needle.
 16. (canceled)
 17. The solid dose carrier according to claim 12 wherein the solid dose carrier is capable of delivering single or multiple doses either consecutively or simultaneously.
 18. The solid dose carrier according to claim 12 wherein the solid dose carrier further comprises a solid dose which is seated on or around the distal portion of the carrier. 19-25. (canceled)
 26. A method of manufacturing a solid dose as defined in claim 1 comprising the following steps: (i) providing the solid dose ingredients; and (ii) shaping the solid dose.
 27. The method according to claim 26 wherein the shaping step involves using a method selected from wet casting, direct compression molding or extrusion.
 28. The method according to claim 26 wherein the shaping step involves compression molding using a multipart tool.
 29. The method according to claim 28 further comprising a step of forming a hollow core of the solid dose.
 30. The method according to claim 29 wherein the method further comprises the steps of (i) placing the solid dose ingredients into a multipart die; (ii) pressing a punch section comprising a pin into the die section to form the hollow core of the solid dose; (iii) optionally rotating either the pin or the die multiparts; and (iv) ejecting the formed solid dose from the die. 31-33. (canceled) 